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A new catalytic aldol-type addition of cyclopropanecarboximides to aldehydes via iodide-mediated ring-opening is presented. The reaction was found to be catalyzed at 0 degrees C using either a Sc(OTf)3/NaI system or ScI3. Stereoselective formation of alpha,alpha-disubstituted enolates occurred in situ. gamma-Lactams bearing alpha-carbonyl quaternary stereocenters were obtained in 97-57% yield and dr = 90:10-80:20 after ring closure.

Design and applications of multimetallic bifunctional asymmetric catalysts based on the proximity-effect-control concept are described. Suitable design of chiral ligands and selection of metals wer...

A catalytic asymmetric anti -selective nitroaldol reaction with a neodymium–sodium heterobimetallic catalyst is described. A readily accessible amide ligand works efficiently as a chiral platform for the Nd/Na heterobimetallic catalyst in the reaction of various aldehydes and nitroethane, affording anti -1,2-nitro alkanols in good diastereo- and enantioselectivity.

Oseltamivir, a widely used anti-influenza drug, inhibits virus neuraminidase. A mammalian homologue of this enzyme is expressed in the brain, yet the effect of oseltamivir on central neurons is largely unknown. Patch-clamp recordings ex vivo revealed that oseltamivir enhanced spike synchronization between hippocampal CA3 pyramidal cells. Time-lapse multineuron calcium imaging revealed that oseltamivir and its active metabolite evoked synchronized population bursts that recruited virtually all neurons in the network. This unique, so-far-unknown, event was attenuated by muscarinic receptor antagonist. Thus, oseltamivir is a useful tool for investigating a new aspect of neural circuit operation.Supplementary Fig. and movie: available only at http://dx.doi.org/10.1254/jphs.SC0070467 Keywords:: oseltamivir, functional multineuron calcium imaging, network excitability

Chiral CuF-catalyzed asymmetric allylation of ketones and ketimines is described. Nucleophile activation via transmetallation (allylboronate to allylcopper), which is facilitated by a cocatalyst [La(O i Pr)3 or LiO i Pr], is key for these reactions. A CuOTf-3KO t Bu-DUPHOS complex is a comparably effective catalyst that reduces the required amount of chiral phosphines.

We report a direct catalytic asymmetric Mannich-type addition of α,β-unsaturated γ-butyrolactam to α-ethoxycarbonyl ketimines promoted by a soft Lewis acid/Bronsted base cooperative catalyst. A thiophosphinoyl group on the nitrogen of ketimines was crucial for both electrophilic activation and α-addition of γ-butyrolactams. The obtained aza-Morita-Baylis-Hillman-type products bear an α-amino acid architecture with a tetra-substituted stereogenic center.

In polytocous animals, blastocysts are evenly distributed along each uterine horn and implant. The molecular mechanisms underlying these precise events remain elusive. We recently showed that lysophosphatidic acid (LPA) has critical roles in the establishment of early pregnancy by affecting embryo spacing and subsequent implantation through its receptor, LPA3. Targeted deletion of Lpa3 in mice resulted in delayed implantation and embryo crowding, which is associated with a dramatic decrease in the prostaglandins and prostaglandin-endoperoxide synthase 2 expression levels. Exogenous administration of prostaglandins rescued the delayed implantation but did not rescue the defects in embryo spacing, suggesting the role of prostaglandins in implantation downstream of LPA3 signaling. In the present study, to know how LPA3 signaling regulates the embryo spacing, we determined the time course distribution of blastocysts during the preimplantation period. In wild-type (WT) uteri, blastocysts were distributed evenly along the uterine horns at Embryonic Day 3.8 (E3.8), whereas in the Lpa3-deficient uteri, they were clustered in the vicinity of the cervix, suggesting that the mislocalization and resulting crowding of the embryos are the cause of the delayed implantation. However, embryos transferred singly into E2.5 pseudopregnant Lpa3-deficient uterine horns still showed delayed implantation but on-time implantation in WT uteri, indicating that embryo spacing and implantation timing are two segregated events. We also found that an LPA3-specific agonist induced rapid uterine contraction in WT mice but not in Lpa3-deficient mice. Because the uterine contraction is critical for embryo spacing, our results suggest that LPA3 signaling controls embryo spacing via uterine contraction around E3.5.

The development of an efficient catalytic system for the direct addition of acetonitrile under mild amine basic conditions is described. A cooperative catalysis of CpRu complex, DBU, and NaPF6 enables chemoselective and catalytic generation of nucleophiles from barely acidic acetonitrile, which is integrated into the addition to aldehydes, imines, and activated ketones. Mechanistic investigations revealed that the three catalyst components work together to achieve high catalytic efficiency.

A general method for direct alkynylation of trifluoromethyl ketones was developed by using CuO(t)Bu-xantphos or phenanthroline complexes as catalysts. The ligands significantly enhanced the catalyst activity. In addition, KOTf, generated in the catalyst preparation step, exhibited some acceleration effects. A preliminary extension to a catalytic enantioselective CF3-substituted tertiary propargyl alcohol synthesis (up to 52% ee) is also described.

A highly congested bicyclo[3.3.1]nonanone core of polycyclic polyprenylated acylphloroglucinols was constructed using a stereoselective Claisen rearrangement and an intramolecular aldol reaction as the key steps. The stereochemistry of C-4 appeared to control the ground state conformation of the cyclohexenone core, which determined the diastereoselectivity in the Claisen rearrangement.

New chiral ligands (4 and 5) for polymetallic asymmetric catalysts were designed based on the hypothesis that the assembled structure should be stable when made from a stable module 8. A metal–ligand=5:6+μ-oxo+OH complex was generated from Gd(OiPr)3 and 4 or 5, and this complex was an improved asymmetric catalyst for the desymmetrization of meso-aziridines with TMSCN and conjugate addition of TMSCN to α,β-unsaturated N-acylpyrroles, compared to the previously reported catalysts derived from 1–3. These two groups of catalysts produced opposing enantioselectivity even though the ligands had the same chirality. The functional difference in the asymmetric catalysts is derived from differences in the higher-order structure of the polymetallic catalysts.

A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized delta-lactones were produced in the presence of a catalytic amount of the Cu(OAc)2-DIFLUORPHOS complex through three-component assembly of dialkylzincs, allenic esters, and unactivated ketones. This CAMCR constructs two C-C bonds and one tetrasubstituted chiral center simultaneously. Conjugate addition of alkylcopper species to an allenic ester produced highly active copper enolate in situ, and the successive asymmetric aldol addition to ketones followed by lactonization afforded the desired products. The addition of MS4A and Lewis base (Ph2S=O, DMSO, or HMPA) is important for obtaining a high yield, with suppression of the undesired alpha-addition pathway. Control/crossover experiments suggest that the addition of a Lewis base facilitated the retro-aldol reaction of the alpha-adducts (proofreading effect). The ketone and copper enolate generated through the retro-aldol reaction were converted to the desired lactone through the gamma-aldol pathway, which was trapped by irreversible lactone formation.

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)3/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not suitable for acyclic α,β-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve enantioselectivity, and a La(O-iPr)3/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good yield and enantioselectivity (up to 96% ee).

Our third generation synthesis of Tamiflu was achieved in 12 steps from commercially available starting materials, using the Diels–Alder reaction and Curtius rearrangement as key steps.

Catalytic intermolecular hydroamination of vinyl arenes is described. Our initial investigation revealed that a Bi(OTf)3/[Cu(CH3CN)4]PF6 system previously developed for catalytic intermolecular hydroamination of 1,3-dienes was suitable for hydroamination of a styrene with sulfonamides, but the substrate generality of this system was unsatisfactory. Several metals were screened to expand the substrate scope, and a new Hf(OTf)4/[Cu(CH3CN)4]PF6 system was determined to be highly suitable. The combination of Hf(OTf)4 and [Cu(CH3CN)4]PF6 efficiently promoted the hydroamination of various vinyl arenes, including less-reactive vinyl arenes with electron-withdrawing groups. This strategy was applied to sulfonamides, carbamates, and carboxamides, and products were obtained in up to 99 % yield with 0.3–10 mol % catalyst loading.

Based on the concept of bifunctional asymmetric catalysis, chiral ligands containing a carbohydrate scaffold were designed. Rare earth metal complexes of the ligands produced general and practical catalytic enantioselective cyanation of ketones and ketoimines. Structural studies of the asymmetric catalysts revealed that the active catalysts are polymetallic complexes containing higher-order structures. The higher-order structure determines the function (activity and enantioselectivity) of the catalysts. The thus-developed catalytic enantioselective methods for the synthesis of tetrasubstituted carbons were applied to the synthesis of biologically active molecules. Catalytic asymmetric synthesis of fostriecin and its analog, lactacystin, Tamiflu®, and garsubellin A are described.

It is found that the thioamide moiety is crucial to promote both the efficient enolization of thiolactam pronucleophiles and the subsequent stereoselective conjugate addition to α,β-unsaturated thioamides.

Caprazamycin B was successfully synthesized via caprazol. In the present synthesis, the choices of the segment coupling conditions and protecting groups were unexpectedly narrow. Only Shiina’s protocol provided the ester linkage between the unreactive secondary hydroxyl group on the diazepanone ring system and the side chain moiety (western zone). Upon final global deprotection, hydrogenolysis conditions were compatible with substructures that are unstable under acidic and basic environments.

The asymmetric aldol reaction of α-aza-indolinylamide (I) with aldehydes is studied in the presence of mesitylcopper as catalyst.

An efficient catalytic system is developed for the Mannich-type reaction of imines (I) with benzyl isocyanide.

Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Bronsted base cooperative catalyst allows for an efficient stereoselective coupling of N-alkylidene-α-aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra- and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading.

A heterogeneous catalyst is produced by self-assembly of an amide-based chiral ligand in multiwalled carbon nanotube fibres by addition of erbium(III) isopropylate.

Thioamides are the preferred pronucleophiles for direct catalytic asymmetric aldol reactions in the context of soft Lewis acid/hard Brønsted base cooperative catalysis., Thioamides are the preferred pronucleophiles for direct catalytic asymmetric aldol reactions in the context of soft Lewis acid/hard Brønsted base cooperative catalysis. In-depth investigation of this proton-transfer catalysis, which is virtually in equilibrium, revealed that the prominence of the retro-aldol reaction depended on the substrate combination. The retro-aldol reaction is a serious issue in direct aldol reactions because the product distribution, including enantiomers and diastereomers, is governed by thermodynamic parameters, and the aldol products are obtained in much lower stereoselectivity compared with the kinetically controlled process. Herein we report the beneficial effect of an additive with a functional group architecture similar to that of the aldol adduct that suppresses the retro-aldol reaction by competitively binding to the catalyst. Strategic use of the additive led to high stereoselectivity, even when the combination of substrates was prone to the retro-aldol reaction.

Recent progress (post-2010) in the field of metal-catalyzed asymmetric C–C bond-forming reactions using ketimines as electrophiles is reviewed. Compared with the corresponding aldimines, ketimines ...

The total synthesis of NBRI16716B (2), a naturally occurring modulator of tumor-stroma interactions, was successfully achieved. Using this synthetic route, a dehydroxy analogue (21) and a derivative lacking the 5-hydroxy-3-methylpentenoyl side chain (22) became accessible. A preliminary structure-activity relationship study to unveil the structural requirements for selective inhibition of tumor cells cocultured with stromal cells revealed that both of the hydroxamate structures of 2 are indispensable, whereas the 5-hydroxy-3-methylpentenoyl side chain is not essential.

The scalable Mannich-type reaction transforms both aromatic and aliphatic N-Boc imines into β-amino acids possessing α-CF3 stereogenicity.

Direct catalytic addition of alkylnitriles to aldehydes allows for an atom-economical access to β-hydroxynitriles under proton transfer conditions.

The bis(hydroxyphenyl)diamide architecture constitutes as a privileged ligand that promotes a number of catalytic asymmetric transformations in combination with rare-earth metals. A new diamide analog armed with a carbene catalytic function derived from a thiazolium unit was designed, synthesized, and applied to the catalytic asymmetric intramolecular Stetter reaction. Cooperative work between the carbene function and hydrogen bonding interactions was suggested to give the enantioenriched chroman derivatives.

Helicobacter pylori growth medium is usually supplemented with horse serum (HS) or FCS. However, cyclodextrin derivatives or activated charcoal can replace serum. In this study, we purified self-growth-inhibiting (SGI) compounds from H. pylori growth medium. The compounds were recovered from porous resin, Diaion HP-20, which was added to the H. pylori growth medium instead of known supplements. These SGI compounds were also identified from 2,6-di-O-methyl-β-cyclodextrin, which was supplemented in a pleuropneumonia-like organisms broth. The growth-inhibiting compounds were identified as lauric acid (LA) and 7-(Z)-tetradecenoic acid [7-(Z)-TDA]. Although several fatty acids had been identified in H. pylori, these specific compounds were not previously found in this species. However, we confirmed that these fatty acids were universally present in the cultivation medium of the H. pylori strains examined in this study. A live/dead assay carried out without HS indicated that these compounds were bacteriostatic; however, no significant growth-inhibiting effect was observed against other tested bacterial species that constituted the indigenous bacterial flora. These findings suggested that LA and 7-(Z)-TDA might play important roles in the survival of H. pylori in human stomach epithelial cells.

Catalytic asymmetric synthesis of Tamiflu, an important antiinfluenza drug, was achieved. After the catalytic enantioselective desymmetrization of meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the C=C double bond were introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile. This second generation route of Tamiflu is more practical than our previously reported route. [reaction: see text].

Catalytic asymmetric epoxidation of α-methyl α,β-unsaturated carboxylic acid derivatives was achieved using anilide as a template. The Pr(Oi-Pr)3-6,6′-Ph-BINOL complex (10 mol%) with a Ph3P(O) (30 mol%) additive promoted the epoxidation of anilides in up to 99% yield and 88% ee. For α-methyl-β-Ph α,β-unsaturated anilide, the Gd(Oi-Pr)3-6,6′-I-BINOL complex (10 mol%) with Ar3P(O) (30 mol%, Ar = 4-methoxyphenyl) was suitable, giving epoxide in 87% yield and 78% ee.

Full details of syn-selective catalytic asymmetric direct Mannich-type reactions of aromatic and heteroaromatic hydroxy ketones promoted by Y[N(SiMe3)2]3/linked-BINOL complexes are described. From ...

The tricyclic core of 5a-capnellenols was synthesized using an asymmetric Heck reaction-carbanion capture process and an intramolecular nitrile oxide cycloaddition as key ring construction steps. Moreover, the desired C5-α-OH product was obtained through a retroaldol and aldol epimerization process of the C5-β-OH tricyclic compound.

The elucidation of specific functions of protein kinase C (PKC) subtypes in physiological processes is an important challenge for the future development of new drug targets. Subtype-selective PKC agonists and antagonists are useful biological tools for this purpose. Most of the currently used PKC modulators elicit their activities through binding to the ATP binding site of PKC, which shares many features with other kinases. PKC modulators that target the PKC regulatory domain are considered to be advantageous in terms of selectivity, because the structure of the regulatory domain is intrinsic to each PKC subtype. In this paper, we describe the identification of new potent and conventional PKC-selective inhibitors that target the regulatory domain. The inhibitors contain a phorbol skeleton, a naturally occurring potent and selective PKC regulatory domain binder, with a perfluorinated alkyl group and a polyether hydrophilic chain on a terephthaloyl aromatic ring at the C12 position. Both of these substituents are essential for the potent inhibitory activity. Specifically, the binding affinity between PKC and the phorbol ester analogues was improved by an electron-deficient aromatic ring at C12. This finding cannot be explained by the previously proposed binding model and suggests a new binding mode between phorbol esters and PKC.

A new method for the catalytic enantioselective alkenylation and arylation of aldehydes involves the activation of alkenyl and aryl boronates by a catalytic amount of the Cu(I)F-DTBM-segphos complex through transmetalation, generating novel alkenyl and aryl copper species. These reagents act as the actual nucleophile. A range of aldehydes can be converted into optically active secondary allyl alcohols or diaryl methanols with excellent enantioselectivity. The appropriate choice of additives, depending on the substrate, is critical to ensure high yields of products. These additives possibly modulate the catalyst turnover step from copper alkoxide intermediates generated by the addition of organocopper reagents to aldehydes.

A direct catalytic asymmetric Mannich-type reaction of isomerizable aliphatic imines is described. A Et2Zn/(S,S)-linked-BINOL complex was suitable for chemoselective enolate formation from a hydroxyketone in the presence of isomerizable aliphatic N-diphenylphosphinoyl imines. The reaction proceeds smoothly and β-alkyl-β-amino-α-hydroxyketones were obtained in good yield and high enantioselectivity (up to 99% ee), albeit in modest to low diastereoselectivity.

Development of metal/linked-BINOL complexes and their applications in direct catalytic asymmetric Mannich-type reactions of hydroxyketones are reviewed. A Et 2 Zn/linked-BINOL complex was effective for diastereo- and enantioselective synthesis of β-amino alcohols. By choosing the proper protective groups on the imine nitrogen, either anti - or syn -β-amino alcohol was obtained in excellent enantioselectivity (up to >99.5% ee) using the same zinc catalysis. Y{N(SiMe 3 ) 2 } 3 /linked-BINOL complex was effective for various hydroxyketones, affording syn -β-amino alcohols with high enantioselectivity (up to 98% ee). To broaden the nucleophile scope to carboxylic acid derivatives, N -acylpyrrole was utilized as an ester equivalent donor. In(O- i Pr) 3 /linked-BINOL complex was effective for generating an In-enolate from N -acylpyrrole in situ, giving Mannich adducts with high enantioselectivity (up to 98% ee).

A highly enantioselective cyano-phosphorylation of aldehydes catalyzed by a YLi 3 tris(binaphthoxide) complex YLB 1 is described. The slow addition of diethyl cyanophosphonate 4 to aldehydes 5 in the presence of YLB 1 (10 mol %), H 2 O (30 mol %), tris(2,6-dimethoxyphenyl)phosphine oxide 3a (10 mol %), and BuLi (10 mol %) afforded cyanohydrin O -phosphates 6 in up to 98% yield and 97% ee. Mechanistic studies revealed that the addition of cyanide to aldehydes is irreversible and determines the enantioselectivity. The reaction mechanism is also discussed in detail.

Total synthesis of (+)-lactacystin, a potent and selective proteasome inhibitor, was accomplished using a catalytic enantioselective Strecker reaction of a ketoimine as the initial key step. An enone-derived N-phosphinoyl ketoimine 7 was selected as a stable masked alpha-hydroxy ketoimine analogue. Excellent enantioselectivity (98% ee) and practical catalyst activity were produced under the optimized catalyst preparation method using 2.5 mol % Gd{N(SiMe3)2}3 as a metal source and 3.8 mol % D-glucose-derived ligand 8. This reaction was conducted on a 5 g scale. The chiral tetrasubstituted C-5 carbon efficiently controlled the stereochemistry of the other three chiral centers of lactacystin. Chelation-controlled Meerwein-type reduction of ketone 5 using i-PrMgBr (originally reported by Kang in a related substrate) selectively produced the desired secondary alcohol at the C-9 position. The C-6 hydroxy and C-7 methyl groups were introduced via a silyl conjugate addition followed by the Tamao oxidation and Donohoe methylation, respectively, in a highly stereoselective manner. A practical amount of enantiomerically pure clasto-lactacystin beta-lactone (2), the biologically active form of (+)-lactacystin, can be synthesized using this route. clasto-Lactacystin beta-lactone (2) was converted to (+)-lactacystin following the reported procedure.

Asymmetric catalysis is a powerful component of modern synthetic organic chemistry. To further broaden the scope and utility of asymmetric catalysis, new basic concepts for the design of asymmetric catalysts are crucial. Because most chemical reactions involve bond-formation between two substrates or moieties, high enantioselectivity and catalyst activity should be realized if an asymmetric catalyst can activate two reacting substrates simultaneously at defined positions. Thus, we proposed the concept of bifunctional asymmetric catalysis, which led us to the design of new asymmetric catalysts containing two functionalities (e.g. a Lewis acid and a Brønsted base or a Lewis acid and a Lewis base). These catalysts demonstrated broad reaction applicability with excellent substrate generality. Using our catalytic asymmetric reactions as keys steps, efficient total syntheses of pharmaceuticals and their biologically active lead natural products were achieved.

Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.

Chiral Y{N(SiMe3)2}3/linked-BINOL catalyst generated Y-enolate in situ from various hydroxyketones (R2 = aryl, heteroaryl). β-Amino-α-hydroxy ketones (R1 = aryl, heteroaryl, alkenyl) were obtained ...

New chiral bidentate diphenylphospholanes were designed targeting a catalytic enantioselective aldol reaction to ketones. Ligands 5l and 5m having cis -2-butenyl and cyclopropyl groups at the linker part, respectively, were identified as effective chiral ligands for a CuF-catalyzed enantioselective aldol reaction to ketones. Catalysts prepared from CuF·3PPh 3 ·2EtOH and these ligands produced ketone aldol products with up to 66% ee, which is promising particularly for this extremely difficult and important catalytic enantioselective carbon–carbon bond forming reaction. The enantioselectivity was strongly dependent on the linker structure. Construction of a deep chiral pocket around the copper metal with stable bidentate chelation is the key to meaningful enantioinduction.